Adamantyl pyran-4-one derivatives and their in vitro antiproliferative activity

Article abstract of DOI:10.1007/s11030-019-09948-1

Abstract: Pyran-4-one (maltol, kojic acid and chlorokojic acid 1) esters of adamantan-1-ylacetic acid were prepared through efficient synthetic routes in good yields and evaluated for their in vitro antiproliferative activity on four cancer cell lines: K562 (chronic myelogenous leukemia), HeLa (cervical cancer), Caco-2 (colorectal adenocarcinoma) and NCI-H358 (bronchioalveolar carcinoma). The results indicate that the presence and the position of the adamantyl acyl group or chlorine atom are the necessary requirement for antitumor activity of pyranone systems. Derivatives of kojic acid with either free (compounds 1 and 8) or acylated 5-OH group (compounds 2 and 9) have shown good-to-moderate activity (IC₅₀ values ranging from 13.1 to 43.0?μM) on all cell lines. Adamantyl kojic acid derivative 5 with a free OH group on the position 2 showed activity only on the K562 cell line. It seems that removal of halogen or adamantyl unit from position 2 elicits antileukemic activity, as observed in compound 5. The positive influence of the adamantyl unit was also observed on a 3-OH acylated derivative of maltol I which was also selectively active on the same cell line. 5-O-benzylated adamantyl compounds 6 and 7 and unmodified starting pyranones were found to be inactive. Antibacterial activity of compounds was also evaluated on S. aureus ATCC 13709, M. catarrhalis ATCC 23246, E. faecalis ATCC29212 and E. coli TolC-Tn10, but no activity was observed (MIC values 128–256?μg/mL). Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11030-019-09948-1

Molecular Diversity
https://doi.org/10.1007/s11030-019-09948-1
ORIGINAL ARTICLE
Adamantyl pyran‑4‑one derivatives and their in vitro antiproliferative
activity
Vesna Petrović Peroković1 · Željka Car1 · Andrea Usenik1 · Teuta Opačak‑Bernardi2 · Andrea Jurić3 · Srđanka Tomić1
Received: 6 February 2019 / Accepted: 27 March 2019
© Springer Nature Switzerland AG 2019
Abstract
Pyran-4-one (maltol, kojic acid and chlorokojic acid 1) esters of adamantan-1-ylacetic acid were prepared through efcient
synthetic routes in good yields and evaluated for their in vitro antiproliferative activity on four cancer cell lines: K562
(chronic myelogenous leukemia), HeLa (cervical cancer), Caco-2 (colorectal adenocarcinoma) and NCI-H358 (bronchio-
alveolar carcinoma). The results indicate that the presence and the position of the adamantyl acyl group or chlorine atom
are the necessary requirement for antitumor activity of pyranone systems. Derivatives of kojic acid with either free (com-
pounds 1 and 8) or acylated 5-OH group (compounds 2 and 9) have shown good-to-moderate activity (IC50 values ranging
from 13.1 to 43.0 μM) on all cell lines. Adamantyl kojic acid derivative 5 with a free OH group on the position 2 showed
activity only on the K562 cell line. It seems that removal of halogen or adamantyl unit from position 2 elicits antileukemic
activity, as observed in compound 5. The positive infuence of the adamantyl unit was also observed on a 3-OH acylated
derivative of maltol I which was also selectively active on the same cell line. 5-O-benzylated adamantyl compounds 6 and
7 and unmodifed starting pyranones were found to be inactive. Antibacterial activity of compounds was also evaluated on
S. aureus ATCC 13709, M. catarrhalis ATCC 23246, E. faecalis ATCC29212 and E. coli TolC-Tn10, but no activity was
observed (MIC values 128–256 µg/mL).
Graphical abstract
K562
Comp.
R
R'
IC50 [µM]
13.1 1
Cl
OH
C(O)CH2Ad
C(O)CH2Ad
H
2
5
8
9
29.1 1.9
16.3 2.7
24.3 0.3
OC(O)CH2Ad
Ad = adamantan-1-yl
OC(O)CH2Ad C(O)CH2Ad
Keywords Kojic acid · Maltol · Adamantyl · Antiproliferation · Cancer
Introduction
Kojic acid (5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one,
Fig. 1), a chelating compound and a common fungal metabo-
lite isolated frst from fungus Aspergillus oryzae in 1907,
is known to inhibit the catecholase activity of tyrosinase,
the rate-limiting essential enzyme in the biosynthesis of the
skin pigment melanin [1]. Therefore, it is widely used pri-
marily in the preparation of cosmetic biomaterials and skin
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11030-019-09948-1) contains
supplementary material, which is available to authorized users.
* Željka Car
zcar@chem.pmf.hr
Extended author information available on the last page of the article
Vol.:(0123456789)
1 3

Molecular Diversity
cancer cell lines [17] where four derivatives were singled
out as the most potent compounds (IC50 values ranging
from 0.3 to 7.0 µM). The starting material for the prepara-
tion of pyridinones is usually pyranone precursors, such as
commercially available maltol and kojic acid. Adamantyl
derivatives of maltol have not been yet reported to the best
of our knowledge, but adamantyl derivatives of kojic acid
have been mentioned in this decade as potential inhibitors
of copper-containing enzyme, tyrosinase. Many inhibitors
of tyrosinase have been synthesized and used as depigment-
ing agents for the treatment of hyperpigmentation and as
antibrowning agents in vegetables and fruits. As already
mentioned, kojic acid is a well-known tyrosinase inhibitor,
but its inhibitory activity is not potent enough for the above
purposes. Therefore, several kojic acid ester and thioether
derivatives have been synthesized, usually by modifcation
of the C-2 hydroxyl group for that purpose [10]. Some of the
prepared derivatives also contained adamantyl moiety either
directly connected to kojic acid through ester or thioether
bond [18] or polyphenol units containing adamantane moi-
eties were coupled with kojic acid [10]. Unfortunately,
in the mushroom tyrosinase assay, adamantyl structural
motifs were not responsible for inhibitory activity of com-
pounds. The thioether linkage and fexible, simple alkyl and
cycloalkyl groups appeared to be critical factors.
Fig. 1 Structural formula of the two naturally occurring pyran-4-one
compounds—kojic acid and maltol
care products. Numerous studies also showed that kojic acid
and its derivatives exhibit other various biological activi-
ties, such as antioxidant [2], antibacterial [1, 3, 4], antitumor
[1, 5–8] anticonvulsant [9] and anti-infammatory activity
[10]. Various kojic acid derivatives were evaluated for their
in vitro antileukemic activity on L1210 murine leukemia
and K562 human leukemia cell lines [5] and displayed IC50
concentrations in low micromolar range.
Maltol (3-hydroxy-2-methyl-4H-pyran-4-one, Fig. 1) is
a naturally occurring compound widely used as a favoring
agent. Similarly like kojic acid, maltol exhibits many practi-
cal applications primarily in food, cosmetic and pharmaceu-
tical industry. Since it is also a metal iron chelator, it is often
used in drugs such as vanadylmaltolate for the treatment
of diabetes, and ferric trimaltol for the treatment of iron
defciency anemia [11]. It has been reported that maltol has
a neuroprotective efect through its antioxidant properties
and antiapoptotic efects in human neuroblastoma cells [11].
Furthermore, maltol suppressed the tumor growth of H22
transplanted tumor in vivo by improving the immune func-
tions, inducing apoptosis and inhibiting angiogenesis [12].
Both maltol and kojic acid are often used as cheap start-
ing material in the synthesis of many other biologically
active compounds such as chlorokojic acid, allomaltol,
pyromeconic acid and various pyridinone derivatives. They
contain a promising polyfunctional heterocyclic skeleton
with several important centers enabling additional reactions
like oxidation, reduction, alkylation, acylation, nucleophilic
and electrophilic substitution, Michael addition with a ring
opening and chelation [13]. Thus, various moieties were
introduced to their structures in an efort to improve their
wide range of biological activities [13, 14].
In view of our previous fndings on the pyridinone deriva-
tives [17] as well as our continuous investigation of their bio-
logical activity [19, 20], we wanted to extend our research
and further explore the infuence of the adamantyl moiety on
the biological activities of pyranone systems as well.
Result and discussion
As pointed out, the presence and adequate position of
the adamantyl moiety connected through the ester and/or
amide bond on the pyridinone skeleton of N-aryl-substituted
pyridin-4-ones infuenced their antitumor in vitro activities
[17]. Diadamantyl derivatives and their monoadamantyl
analogues with the free iron chelation site were compounds
with the highest activity on all investigated cancer cell lines
(Fig. 2).
A non-natural adamantane structure is often used to
modulate physiological response of many biologically active
compounds and drugs primarily by changing absorption,
distribution, metabolism or excretion properties of a mol-
ecule. Adamantyl group can also bind to a hydrophobic site
in an enzyme and to act as an inhibitor or afect ion channels
by disrupting the transmembrane fow [15, 16]. We have
already shown that the presence and adequate position of
the adamantane moiety on the pyridinone skeleton in the
adamantylated series of N-aryl-substituted pyridin-4-ones
infuence greatly their antitumor in vitro activities on several
Thus, analogous pyran-4-one esters of adamantan-
1-ylacetic acid needed for this study were prepared in sev-
eral reaction steps starting from the commercially available
pyranones, maltol and kojic acid. The key esterifcation step
used for the preparation of monoadamantyl derivatives I,
2, 4, 7 and diadamantyl compound 9 was performed under
Steglich conditions, using EDC×HCl/DMAP combination
of reagents, in moderate-to-good yields (60–80%, Schemes 1
and 2). Chlorokojic derivative 1 was obtained in a very good
yield (85%) from kojic acid. Out of many procedures known
in the literature [9, 14, 18, 21–23] for the preparation of 1,
1 3

Molecular Diversity
obtained with DHP and p-TsOH×H2O as reagents, in mod-
erate yield (47%), and protection was subsequently removed
using p-TsOH×H2O in order to prepare adamantyl deriva-
tive 5 (35%).
Benzyl protection was selectively introduced on the
position 5 using classical Williamson ether synthesis, and
5-benzyloxy derivative 6 (84%, Scheme 2) was obtained
from kojic acid and benzyl chloride (1.1 equiv.) in basic
conditions [26]. The protection was removed after Steglich
esterifcation step using a known dealkylating agent, strong
Lewis acid boron tribromide. The reaction conditions in this
step required careful tuning since used in excess or used in
prolonged reaction times this reagent removes the acyl group
as well. The hydrogenolysis procedure was also tested for
the removal of the benzyl ether group in 7, but the reaction
resulted in overall hydrogenation of the whole conjugated
pyranone system even in mild conditions and short reaction
times (3.45×104 Pa, 10% Pd/C, 10 min).
Fig. 2 Four most potent N-aryl-substituted pyridin-4-one derivatives
with IC50 concentrations from 0.3 to 7.0 µM [17]
the ones which can be performed without the addition of
organic solvent and in good yields were chosen [21–23].
In order to selectively prepare the monoadamantyl kojic
acid derivatives 5 and 8, with the acyl unit on the position
5 or 2 of the pyranone ring, respectively, protecting groups
were used. Tetrahydropyranyl ether group was chosen for
the selective protection of the primary hydroxyl group of
the starting kojic acid, and it was introduced or removed
accordingly using known and efective procedures [24–26].
Thus, 2-tetrahydropyranyloxymethyl derivative 3 was
Mannich bases of substituted piperazine with kojic and
chlorokojic acid have been described as antimicrobial agents
with signifcant activity against Gram-positive and Gram-
negative bacteria [4, 21, 23]. There are several published
data for the in vitro antibacterial activity on Gram-positive
and Gram-negative strains for natural pyranone products,
kojic acid and maltol [1, 3, 13, 27]. Since maltol is a known
food favoring agent, an extensive screening for its anti-
fungal and antibacterial properties was already done and
Scheme 1 Reagents and conditions: (a) (i) AdCH2COOH, DMAP,
EDC×HCl, dry CH2Cl2 (for I and 4) or mixture of dry solvents
CH2Cl2/dioxane (for 2), 0 °C, 30 min, (ii) rt, 24 h, 77% (I), 66% (2),
80% (4); (b) SOCl2, Ar, 3 h, 85% (1); (c) DHP, p-TsOH×H2O, dry
CH2Cl2, 1 h, 47% (3); (d) p-TsOH×H2O, CH3OH, 0 °C, 1 h, 35% (5)
1 3

Molecular Diversity
Scheme 2 Reagents and conditions: (a) BnCl, 11 M NaOH, CH3OH, refux, 24 h, 84% (6); (b) (i) AdCH2COOH, DMAP, EDC×HCl, dry
CH2Cl2, 0 °C, 30 min, (ii) rt, 24 h, 60% (7), 62% (9); (c) BBr3, dry CH2Cl2, 75 min, 70% (8)
published in the literature in order to evaluate its toxicity
for safe application in food industry. Similar screening was
also done for kojic acid since this natural product is used
as skin-whitening agent in cosmetics. Thus, other deriva-
tives used in this study, adamantyl (I, 2, 5, 8, 9) and benzyl
pyranone derivatives (6 and 7) as well as chlorokojic acid 1,
were investigated on two Gram-positive (S. aureus ATCC
13709 and E. faecalis ATCC29212) and two Gram-nega-
tive (M. catarrhalis ATCC 23246 and E. coli TolC-Tn10)
strains for their antibacterial activity with azythromycin as
referenced antibacterial agent. The weak activity of 1 was
the only one observed (MIC values of 128 µg/mL on E.
faecalis ATCC29212, M. catarrhalis ATCC 23246 and E.
coli TolC-Tn10) the result which was comparable to that
already reported in the literature for this compound on some
of these strains [28].
compound have been already attempted by other researchers
[5–8]. Bransova et al. [5] examined a number of halogen-
ated (chloro, bromo and iodo), acylated (acetyl) and/or ether
(methyl and benzyl) kojic acid derivatives for their anti-
leukemic activity on L1210 murine leukemia cell growth.
The most potent compounds were also evaluated on human
leukemia K562 cell line, and the results were comparable.
In general, the halogenated derivatives of kojic acid inhib-
ited cell growth (IC50 values from 3.2 to 20.0 μM on L1210
murine leukemia cells). Kojic acid showed no efect on
L1210 cell growth. Ether (benzyl or methyl group on the
position 5) and acetyl derivatives of kojic acid in general
showed no activity except for the 5-benzyloxy-2-chloro-
methylpyran-4-one which displayed IC50 value of 5.0 μM on
L1210 murine leukemia cells. All results indicated the posi-
tive infuence of halogen atom on the antileukemic activity
of inspected derivatives.
Prepared pyran-4-one esters of adamantan-1-ylacetic acid
were next evaluated for their in vitro antiproliferative activ-
ity (Table 1) on four cancer cell lines: K562 (chronic mye-
logenous leukemia, CML), HeLa (cervical cancer), Caco-2
(colorectal adenocarcinoma), NCI-H358 (bronchioalveolar
carcinoma), as well as on normal cells (MDCK). The Lipin-
ski rules serve as guidelines during drug discovery when
a pharmacologically active structure is optimized stepwise
to increase the activity and selectivity of the compound in
order to maintain drug-like physicochemical properties.
Ideally, according to those guidelines, a drug-like molecule
should have logarithmic values of the partition coefcient
(log P) from −0.4 to 5 to bypass the cell barrier with molec-
ular weight between 180 and 500 [29]. There are several pro-
grams available today for the evaluation of the log P value of
the compounds including ALOGPS 2.1 software which was
used to assess the derivatives in this study [30].
We have chosen the K562 tumor cell line in this study so
we could compare our results with the published data and
furthermore compare the results obtained in our parallel
ongoing structure–activity relationship study on pyridi-
none derivatives. In order to investigate the cell selectiv-
ity of prepared compounds, several other tumor lines were
employed as well as a non-cancerous cell line. As expected,
non-modifed kojic acid showed no activity on all cell lines.
Maltol, a new evaluated pyran-4-on skeleton, also showed
no activity. On the other hand, kojic acid derivatives with
either free (compounds 1 and 8) or acylated 5-OH group
(compounds 2, 5 and 9) showed good-to-moderate in vitro
antiproliferative activity with IC50 ranging from 13.1 to
43.0 μM. Positive infuence of the acyl (adamantan-1-yla-
cetyl) unit was also observed on 3-OH acylated derivative
of maltol I which was selectively active only on the K562
cancer cell line (IC50 33.9 8.4 μM). Therefore, the pres-
ence of adamantyl group or chlorine atom is a prerequisite
Several attempts to improve the anticancer potential of
kojic acid by introducing various chemical moieties to the
1 3

Molecular Diversity
Table 1 Compounds’ calculated log P coefcients, molecular weight
(MW) and IC50 values [μM] evaluated on four cancer cell lines
(K562, chronic myelogenous leukemia; HeLa, cervical cancer; Caco-
2, colorectal adenocarcinoma; and NCI-H358, bronchioalveolar carci-
noma) and MDCK non-cancerous cell line as control
Compound
K562
HeLa
Caco-2
> 100
NCI-H358
> 100
MDCK
> 100
clog Pa
MW
O
OH
> 100
> 100
–0.24
126.11
O
maltol
O
O
Ad
33.9 8.4
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
3.58
302.36
142.11
O
O
I
O
OH
HO
> 100
–1.02
O
kojic acid
O
OH
22.6 5.1 34.9 3.5 26.6 2.8 36.1 2.3
23 2.7
0.28
3.95
2.93
1.51
160.56
336.81
318.36
232.23
Cl
O
1
O
O
O
Ad
Ad
13.1
1
32.2 6.6
> 100
43 5.4
> 100
29.7 3.5 37.6 2.3
Cl
O
O
O
O
2
5
29.1 1.9
> 100
> 100
> 100
> 100
> 100
HO
O
O
OBn
> 100
> 100
HO
O
6
O
OBn
OH
O
70.5 25.4
> 100
> 100
> 100
> 100
4.44
408.49
Ad
O
O
7
8
O
O
16.3 2.7 29.4 4.8 18.4 3.1 30.7 4.1 20.4 1.6
2.75
4.78
318.36
494.62
Ad
O
O
O
O
Ad
O
O
24.3 0.3 31.3 4.5
40 2.3
31.7 5.6 33.8 1.8
Ad
O
O
9
aOctanol–water partition coefcient as computed by ALOGPS 2.1 software [30]
1 3

Molecular Diversity
for antitumor activity of pyranone systems since starting
unmodifed pyranones were found to be inactive. 5-O-ben-
zylated adamantyl derivatives 6 and 7 showed complete
inactivity on all cell lines similarly as 5-O-ether derivatives
evaluated by Bransova et al. [5] which also indicates the
importance of: (1) the position of the adamantan-1-yla-
cetyl group on the pyranone skeleton, (2) the type of acyl
group incorporated since acetyl derivatives evaluated in
previously published data [5] were found to be inactive
and (3) the type of bond (ester vs ether) on the position 5
between the pyranone system and the incorporated moi-
ety. Compound 5 with the adamantyl ester group on the
position 5 was selectively active only on K562 tumor cell
line (IC50 29.1 1.9 μM). It seems that removal of halo-
gen and adamantyl unit from position 2 in structures 2 or
9 elicits selective activity, observed in compound 5. The
presence and the position of the adamantyl unit were also
the important structural parameters that governed antipro-
liferative activity of previously investigated N-aryl-substi-
tuted pyridin-4-ones [17]. It should be also noted that the
presence of the N-aryl part in such systems contributes
additionally to their antiproliferative activities since their
IC50 values on K562 cell line were lower compared to IC50
values of active compounds that are presented in this work
and inspected on the same cell line. Nevertheless, selective
antileukemic activity of compounds I and 5 which also
possess good drug-like physicochemical properties makes
them promising candidates for further structure optimiza-
tion and fne-tuning which could result with even better
biological response. Our primary objective, currently, is a
3D-QSAR study of all results obtained on pyridinone [17]
and pyrone compounds which will, once fnished, provide
us with more precise guidelines in a design of even better
leads.
to 43.0 μM on all cell lines. Maltol derivative I and kojic
acid derivative 5 were selectively active only on K562 tumor
cell line. It seems that the presence and adequate position of
the adamantyl acyl group or chlorine atom are a prerequisite
for antitumor activity of pyranone systems. This is further
substantiated by the complete inactivity of starting unmodi-
fed pyranones and ether 5-O-benzylated adamantyl deriva-
tives 6 and 7. The presence and the position of adamantyl
acyl unit were also the important structural parameters that
governed antiproliferative activity of our previously investi-
gated N-aryl-substituted pyridin-4-one derivatives. Selective
activity of compounds I and 5 which also possess satisfactory
physicochemical properties according to Lipinski rules makes
them promising candidates for further structure optimization
in order to achieve better antileukemic response. Antibacterial
activity of all pyranone adamantyl derivatives was evaluated
on S. aureus ATCC 13709, M. catarrhalis ATCC 23246, E.
faecalis ATCC29212 and E. coli TolC-Tn10, but compounds
were found to be inactive.
Experimental section
General information
Reagents and solvents for the synthesis of compounds were
obtained from commercial sources (mainly Sigma-Aldrich
Corp., Taufkirchen, Germany, and Kemika, Zagreb, Croatia).
When necessary solvents were further purifed and/or dried
using standard methods. Thin-layer chromatography (solvents
and proportions are given in the text) was performed on Fluka
silica gel (60 F 254) plates (0.25 mm), Steinheim, Germany.
Visualization was achieved using UV light at 254 nm. Col-
umn chromatography (solvents and proportions are also given
in the text) was performed on Merck silica gel 60 (70–230
mesh ASTM, Darmstadt, Germany). Melting points were
determined in open capillaries using Büchi B-540 melting
point apparatus (New Castle, DE, USA) and are uncorrected.
1H and DEPTQ NMR spectra were recorded at room tem-
perature on Bruker Avance III HD spectrometer at 400 and
100 MHz, respectively. Deuterated solvents are stated in the
text. Chemical shifts (δ) are given in parts per million (ppm)
downfeld from tetramethylsilane as internal standard (s=sin-
glet, br s=broad singlet, d=doublet, t=triplet and m=multi-
plet). Coupling constants (J) are quoted to the nearest 0.1 Hz.
ESI–MS measurements in a positive ion mode were recorded
on Agilent 6420 instrument (Palo Alto, CA, USA). High-reso-
lution mass spectra (HRMS) were obtained by matrix-assisted
laser desorption/ionization time-of-fight MALDI TOF/TOF
mass spectrometer (4800 Plus MALDI TOF/TOF analyzer,
Applied Biosystems Inc., Foster City, CA, USA) for all tested
compounds.
Conclusion
In continuation of our ongoing research of N-aryl-substituted
pyridinone derivatives, mostly in terms of their antiprolif-
erative and antiadhesive activity, we have also investigated
similar, naturally occurring pyranone systems which are
usually used as a starting material in syntheses of men-
tioned pyridinone compounds. Thus, pyran-4-one esters of
adamantan-1-ylacetic acid were successfully prepared using
afordable and efcient methods in good yields and evalu-
ated for their in vitro antiproliferative activity on four cancer
cell lines (K562, HeLa, Caco-2 and NCI-H358) as well as on
normal cells (MDCK). Compounds with either free (1 and 8)
or acylated 5-OH group (2 and 9) showed good-to-moderate
in vitro antiproliferative activity with IC50 ranging from 13.1
1 3

Molecular Diversity
Synthesis of 2‑(chloromethyl)‑5‑hy‑
droxy‑4H‑pyran‑4‑one (1) [21–23]
Synthesis of 5‑benzyloxy‑2‑hydroxyme‑
thyl‑4H‑pyran‑4‑one (6) [26]
Kojic acid (0.500 g; 3.52 mmol) was placed in a round-
bottom fask which was cooled in an ice bath, and freshly
distilled SOCl2 (7.5 equiv.) was slowly added next. Ice
bath was removed, and the mixture placed under an argon
atmosphere and stirred at room temperature for 3 h. The
reaction was monitored by TLC (diethyl ether). Petroleum
ether was added next, and the crude crystal residue was
fltered of and washed thoroughly with the same solvent.
The product was purifed by column chromatography on
silica gel (diethyl ether).
Kojic acid (1 g, 7.04 mmol) was suspended in methanol
(7 mL), and 11 M aqueous solution of sodium hydroxide
was added next (1.05 mL, 11.55 mmol). To the resulting
solution, benzyl chloride (1.34 mL, 11.70 mmol) was added
dropwise and the solution was refuxed for 24 h and then
cooled. The reaction was monitored by TLC (ethyl acetate/
methanol, 5:1, υ/υ). After cooling, methanol was evaporated
in vacuo and the crude product fltered of and washed exces-
sively with combination of solvents diethyl ether/petroleum
ether, 1:1, υ/υ. The product was fnally purifed by column
chromatography on silica gel (ethyl acetate/methanol, 5:1,
υ/υ).
White solid (0.480 g, yield 85%), m.p. 165.5–166.5 °C,
lit. [21–23] 166–167 °C.
1H NMR (DMSO-d6) δ/ppm: 4.65 (s, 2H, CH2Cl), 6.57
(s, 1H, H-3), 8.12 (s, 1H, H-6), 9.30 (s, 1H, OH).
DEPTQ NMR (DMSO-d6) δ/ppm: 41.20 (CH2Cl),
113.19 (C-3), 140.10 (C-6), 145.97 (C-5), 161.64 (C-2),
173.68 (C=O).
Light yellow solid (1.38 g, yield 84%), m.p.
124.0–126.2 °C, lit. [26] 128–130 °C.
1H NMR (DMSO-d6) δ/ppm: 4.29 (d, 2H, J = 6.1 Hz,
CH2OH), 4.94 (s, 2H, CH2, Bn), 5.68 (t, 1H, J = 6.1 Hz,
OH), 6.32 (s, 1H, H-3), 7.35–7.42 (m, 5H, Ph), 8.17 (s, 1H,
H-6).
ESI–MS: m/z 161.1 [M + H]+.
HRMS Calcd for C6H5ClO3 [M+H]+: 161.0005. Found
160.9997.
DEPTQ NMR (DMSO-d6) δ/ppm: 59.21 (CH2OH),
70.49 (CH2, Bn), 111.08 (C-3), 127.95, 128.02, 128.28 (5
CH, Ph), 136.06 (C, Ph), 141.21 (C-6), 146.48 (C-5), 167.88
(C-2), 173.08 (C=O).
Synthesis of 5‑hydroxy‑2‑tetrahydropyranyloxyme‑
thyl‑4H‑pyran‑4‑one (3) [24, 26]
ESI–MS: m/z 255.1 [M+Na]+.
HRMS Calcd for C13H12O4 [M+H]+: 233.0814. Found
233.0810.
Kojic acid (0.500 g; 3.52 mmol) was suspended in dry
CH2Cl2 (18 mL). 3,4-Dihydro-2H-pyran (DHP, 1.3 equiv.)
and p-TsOH×H2O (0.05 equiv.) were added next. Reaction
mixture was stirred for 1 h at room temperature and moni-
tored by TLC (ethyl acetate). It was extracted three times
with 3% aqueous NaOH, and the combined aqueous layers
were neutralized with 0.5 M NaH2PO4. After extraction
with CH2Cl2, the organic layer was dried over anhydrous
Na2SO4, fltrated and concentrated in vacuo.
General procedure for the preparation of adamantyl
pyran‑4‑one derivatives
An appropriate pyranone derivative (maltol, 1, 3 or 6,
0.200 g of each) was added to a solution of adamantan-
1-ylacetic acid (1 equiv.) and DMAP (0.1 equiv.) in dry
CH2Cl2 (6 mL for the preparation of I, 4 and 7) or mix-
ture of dry solvents CH2Cl2/dioxane (1:1, υ/υ, 6 mL for the
preparation of 2). The mixture was cooled down to 0 °C,
and EDC × HCl (1.1 equiv.) was added next. The solution
was stirred for 30 min at 0 °C and subsequently overnight at
room temperature. The synthesis of diadamantyl derivative
9 from kojic acid (0.200 g) was carried out in an analogous
manner using adamantan-1-ylacetic acid (2 equiv.), DMAP
(0.2 equiv.) and EDC × HCl (2.2 equiv.) in dry CH2Cl2
(6 mL). All reactions were monitored by TLC (ethyl acetate/
methanol, 5:1, υ/υ). Reaction mixture where combination
of solvents was used was prior to extraction concentrated in
vacuo. CH2Cl2 was added next, and the organic layer was
washed twice with 0.2 M HCl, once with saturated aque-
ous NaHCO3, once with water and fnally dried over anhy-
drous Na2SO4. After fltration, the organic extract was con-
centrated in vacuo. The residues were purifed by column
White solid (0.378 g, yield 47%), m.p. 79.6 °C, lit. [26]
94.0 °C.
1H NMR (DMSO-d6) δ/ppm: 1.45–1.55 (m, 4H,
2 × CH2, THP), 1.61–1.76 (m, 2H, CH2, THP), 3.43–3.49
(m, 1H, CH2O, THP), 3.70–3.76 (m, 1H, CH2O, THP),
4.34 (d, 1H, J = 14.1 Hz, Ha, CHaHbO), 4.45 (d, 1H,
J = 14.1 Hz, Hb, CHaHbO), 4.69 (t, 1H, J = 1.8 Hz, CH,
THP), 6.40 (s, 1H, H-3), 8.06 (s, 1H, H-6), 9.15 (s, 1H,
OH).
DEPTQ NMR (DMSO-d6) δ/ppm: 18.68, 24.76, 29.79
(3×CH2, THP), 61.28 (CH2O), 64.26 (CH2O, THP), 97.74
(CH, THP), 111.66 (C-3), 139.61 (C-6), 145.82 (C-5),
164.07 (C-2), 173.70 (C=O).
ESI–MS m/z 249.2 [M + Na]+.
1 3

Molecular Diversity
chromatography on silica gel (ethyl acetate/methanol, 5:1,
υ/υ) giving the corresponding adamantyl derivatives I, 2,
4, 7 and 9.
5‑Benzyloxy‑4H‑pyran‑4‑one‑2‑ylmethyl adaman‑
tan‑1‑ylacetate (7)
White solid (0.211 g, yield 60%), m.p. 133.5–134.1 °C.
1H NMR (DMSO-d6) δ/ppm: 1.56–1.68 (m, 12H, 6 Hα,
6 Hγ, Ad), 1.92 (br s, 3H, Hβ, Ad), 2.14 (s, 2H, CH2Ad),
4.95, 4.96 (2×s, 4H, CH2O and CH2, Bn), 6.46 (s, 1H, H-3),
7.34–7.41 (m, 5H, Ph), 8.23 (s, 1H, H-6).
2‑Methyl‑4H‑pyran‑4‑one‑3‑yl adamantan‑1‑ylacetate (I)
White solid (0.323 g, yield 77%), m.p. 107.0–108.3 °C.
1H NMR (DMSO-d6) δ/ppm: 1.62–1.69 (m, 12H, 6 Hα,
6 Hγ, Ad), 1.95 (br s, 3H, Hβ, Ad), 2.24 (s, 3H, CH3), 2.31
(s, 2H, CH2Ad), 6.40 (d, 1H, J=5.8 Hz, H-5), 8.14 (d, 1H,
J=5.8 Hz, H-6).
DEPTQ NMR (DMSO-d6) δ/ppm: 27.81 (Cβ, Ad), 32.22
(C, Ad), 36.06 (Cγ, Ad), 41.50 (Cα, Ad), 47.50 (CH2Ad),
60.74 (CH2O), 70.49 (CH2, Bn), 113.86 (C-3), 127.95,
128.07, 128,30 (5 CH, Ph), 135.91 (C, Ph), 141.48 (C-6),
146.74 (C-5), 161.59 (C-2), 169.91 (C=O, ester), 172.77
(C=O).
DEPTQ NMR (DMSO-d6) δ/ppm: 14.57 (CH3), 27.87
(Cβ, Ad), 32.38 (C, Ad), 36.07 (Cγ, Ad), 41.34 (Cα, Ad),
47.18 (CH2Ad), 115.78 (C-5), 137.65 (C-2), 155.70 (C-6),
158.84 (C-3), 167.49 (C=O, ester), 170.86 (C=O).
ESI–MS m/z 325.2 [M+Na]+.
ESI–MS m/z 409.2 [M+H]+.
HRMS Calcd for C25H28O5 [M+H]+: 409.2015. Found
409.2016.
HRMS Calcd for C18H22O4 [M+Na]+: 325.1416. Found
325.1409.
5‑Adamantan‑1‑ylacetyloxy‑4H‑pyran‑4‑one‑2‑ylmethyl
adamantan‑1‑ylacetate (9)
2‑(Chloromethyl)‑4H‑pyran‑4‑one‑5‑yl adamantan‑1‑ylac‑
etate (2)
White solid (0.362 g, yield 62%), m.p. 127.5–128.4 °C.
1H NMR (DMSO-d6) δ/ppm: δ 1.57–1.67 (m, 24H, Hγ,
Hα, Ad), 1.94 (br s, 6H, Hβ, Ad), 2.16 (s, 2H, CH2Ad), 2.27
(s, 2H, CH2Ad), 5.00 (s, 2H, CH2), 6.57 (s, 1H, H-3), 8.53
(s, 1H, H-6).
White solid (0.110 g, yield 66%), m.p. 155.5–157.0 °C.
1H NMR (DMSO-d6) δ/ppm: 1.61–1.67 (m, 12H, 6 Hα, 6
Hγ), 1.95 (br s, 3H, Hβ), 2.28 (s, 2H, CH2Ad), 4.73, (s, 2H,
CH2Cl), 6.69 (s, 1H, H-3), 8.57 (s, 1H, H-6).
DEPTQ NMR (DMSO-d6) δ/ppm: 27.90 (Cβ, Ad), 32.44
(C, Ad), 36.08 (Cγ, Ad), 40.89 (Cα, Ad), 41.31 (CH2Cl),
47.18 (CH2Ad), 115.45 (C-3), 140.32 (C-6), 149.68 (C-5),
162.96 (C-2), 167.78 (C=O, ester), 171.64 (C=O).
ESI–MS m/z 695.2 [2M+Na]+.
DEPTQ NMR (DMSO-d6) δ/ppm: δ 28.41, 28.46 (Cβ,
Ad), 32.85, 32.99 (C, Ad), 36.65 (Cγ, Ad), 41.88, 42.10
(Cα, Ad), 47.75, 48.08 (CH2Ad), 61.28 (CH2), 115.45 (C-3),
140.95 (C-5), 149.92 (C-6), 163.44, 168.31 (C=O, esters),
170.51 (C-2), 172.05 (C=O).
HRMS Calcd for C18H21ClO4 [M + Na]+: 359.1026.
Found 359.1019.
ESI–MS m/z 517.3 [M+Na]+.
HRMS Calcd for C30H38O6 [M+H]+: 495.2747. Found
495.2741.
2‑(Tetrahydropyranyloxymethyl)‑4H‑pyran‑4‑one‑5‑yl
adamantan‑1‑ylacetate (4)
Synthesis of 2‑hydroxymethyl‑4H‑pyran‑4‑one‑5‑yl
adamantan‑1‑ylacetate (5)
White solid (0.245 g, yield 80%), m.p. 102.5–103.8 °C.
1H NMR (DMSO-d6) δ/ppm: 1.47–1.57 (m, 4H, 2×CH2,
THP), 1.61–1.70 (m, 14H, CH2, THP; 6 Hα; 6 Hγ), 1.95
(br s, 3H, Hβ), 2.28 (s, 2H, CH2Ad), 3.45–3.50 (m, 1H,
CH2, THP), 3.72–3.78 (m, 1H, CH2, THP), 4.42 (d, 1H,
J = 14.1 Hz, Ha, CHaHbO), 4.52 (d, 1H, J = 14.2 Hz, Hb,
CHaHbO), 4.73 (t, 1H, J=3.3 Hz, CH, THP), 6.51 (s, 1H,
H-3), 8.49 (s, 1H, H-6).
Compound 4 (0.650 g, 0.50 mmol) was dissolved in dry
methanol (20 mL), and the mixture was cooled in an ice
bath to 0 °C.
p-TsOH × H2O (1 equiv.) was added next, and reaction
mixture was stirred for 1 h and monitored by TLC (ethyl
acetate). It was concentrated in vacuo, and cold distilled
water was added next (2–3 mL). Crude product was fltered
of and dried.
DEPTQ NMR (DMSO-d6) δ/ppm: 18.68, 24.74, 29.77
(3 CH2, THP), 27.93 (Cβ, Ad), 32.43 (C, Ad), 36.09 (Cγ,
Ad), 41.34 (Cα, Ad), 47.24 (CH2Ad), 61.34 (CH2O), 64.06
(CH2O, THP), 97.89 (CH, THP), 111.88 (C-3), 140.29
(C-5), 149.24 (C-6), 165.04 (C-2), 167.84 (C=O, ester),
171.67 (C=O).
White solid (0.180 g, yield 35%), m.p. 130.0–131.5 °C.
1H NMR (CDCl3) δ/ppm: 1.65–1.71 (m, 12H, 6 Hα, 6
Hγ), 2.00 (br s, 3H, Hβ), 2.32 (s, 2H, CH2Ad), 3.49 (t, 1H,
J=6.6 Hz, OH), 4.94, (d, 2H, J=6.4 Hz, CH2O), 6.53 (s,
1H, H-3), 7.48 (s, 1H, H-6).
ESI–MS m/z 425.5 [M+Na]+.
DEPTQ NMR (CDCl3) δ/ppm: 28.58 (Cβ, Ad), 33.09 (C,
Ad), 36.62 (Cγ, Ad), 42.12 (Cα, Ad), 48.07 (CH2Ad), 60.62
1 3

Molecular Diversity
(CH2O), 113.09 (C-3), 140.94 (C-5), 147.87 (C-6), 168.43
(C-2), 169.70 (C=O, ester), 173.22 (C=O).
ESI–MS m/z 319.2 [M + H]+.
100 μg/mL streptomycin in a humidifed atmosphere with
5% CO2 at 37 °C. Suspension cells were cultured in RPMI
1640 medium supplemented with 10% fetal bovine serum
(FBS), 2 mM l-glutamine, 1 mM sodium pyruvate, 10 mM
HEPES, 100 U/mL penicillin and 100 μg/mL streptomycin
in a humidifed atmosphere with 5% CO2 at 37 °C. Trypan
blue dye exclusion method was used to assess cell viability
prior to testing.
HRMS Calcd for C18H22O5 [M+H]+: 319.1545. Found
319.1540.
Synthesis of 5‑hydroxy‑4H‑pyran‑4‑one‑2‑ylmethyl
adamantan‑1‑ylacetate (8)
The growth inhibition activity was assessed as
described previously [31, 32]. The cell lines were inocu-
lated onto a series of standard 96-well microtiter plates
on day 0, at 2 × 104 cells/mL (CML, HeLa, Caco-2 and
MDCK). Suspension cells (K562) were seeded at 1 × 105
cells/mL. Test agents were then added in tenfold dilutions
(10−8 to 10−4 M) and incubated for further 72 h. The sol-
vent (DMSO) concentration never exceeded 0.25%. Work-
ing dilutions were freshly prepared on the day of testing.
After 72 h of incubation, the cell growth rate was evalu-
ated by performing the MTT assay, which detects dehy-
drogenase activity in viable cells. After 72 h of incubation
with the tested compounds, MTT (Merck, Germany) was
added. DMSO (Merck, Germany) was used to dissolve the
formed MTT-formazan crystals. Absorbance was meas-
ured at 595 nm using a plate reader (iMark, Bio-Rad,
Hercules, CA, USA). All experiments were performed in
triplicate. The absorbance is directly proportional to the
number of living, metabolically active cells. The percent-
age of growth (PG) of the cell lines was calculated accord-
ing to one or the other of the following two expressions:
If (mean Atest–mean Atzero) ≥ 0, then PG = 100 × (mean
Atest–mean Atzero)/(mean Actrl–mean Atzero) or if (mean
Atest–mean Atzero) < 0, then PG = 100 × (mean Atest–mean
Atzero)/Atzero, where the mean Atzero is the average of optical
density measurements before exposure of cells to the test
compound, the mean Atest is the average of optical density
measurements after the desired period of time, and the
mean Actrl is the average of optical density measurements
after the desired period of time with no exposure of cells
to the test compound. The results are expressed as IC50,
which is the concentration necessary for 50% of inhibi-
tion. The IC50 values for each compound are calculated
from concentration–response curves using linear regres-
sion analysis by ftting the test concentrations that give PG
values above and below the reference value (i.e., 50%).
If, however, for all of the tested concentrations produce
PGs exceeding the respective reference level of efect (e.g.,
PG value of 50), then the highest tested concentration is
assigned as the default value, which is preceded by a “>”
sign. Each test was performed in quadruplicate in at least
two individual experiments.
Compound 7 (0.200 g, 0.49 mmol) was dissolved in dry
CH2Cl2 (20 mL), and the mixture was cooled in an ice bath
to 0 °C. Boron tribromide was added next (BBr3, 1 equiv.
of 1 M solution in dry CH2Cl2). The reaction mixture was
stirred for 75 min and monitored by TLC (ethyl acetate/
methanol, 5:1, υ/υ). It was stopped by the addition of dis-
tilled water (20 mL), and the mixture was stirred vigor-
ously for additional 15 min. The two layers were separated,
and the aqueous layer extracted once with CH2Cl2. Com-
bined organic extracts were dried over anhydrous Na2SO4.
After fltration, the solvent was concentrated in vacuo. The
residue was purifed by column chromatography on silica
gel (ethyl acetate/methanol, 5:1, υ/υ), and the compound
8 was obtained.
White solid (0.108 g, yield 70%), m.p. 120.5–121.9 °C.
1H NMR (CDCl3) δ/ppm: 1.61–1.73 (m, 12H, 6 Hα, 6
Hγ), 1.98 (br s, 3H, Hβ), 2.17 (s, 2H, CH2Ad), 4.91, (s,
2H, CH2O), 6.52 (s, 1H, H-3), 7.85 (s, 1H, H-6).
DEPTQ NMR (CDCl3) δ/ppm: 28.50 (Cβ, Ad), 32.93
(C, Ad), 36.59 (Cγ, Ad), 42.32 (Cα, Ad), 48.37 (CH2Ad),
60.95 (CH2O), 111.15 (C-3), 137.80 (C-6), 145.88 (C-5),
163.07 (C-2), 170.53 (C=O, ester), 173.95 (C=O).
ESI–MS m/z 319 [M + H]+.
HRMS Calcd for C18H22O5 [M+H]+: 319.1545. Found
319.1533.
Cell culturing and 3‑(4,5‑dimethylthia‑
zol‑2‑yl)‑2,5‑diphenyltetrazolium bromide (MTT)
test
The experiments were carried out on four human cell
lines, which are derived from four cancer types and one
non-cancerous cell line (MDCK epithelial). The used cell
lines have been variously sourced and maintained in our
laboratory. All cell lines have been confrmed by pheno-
typing according to ATCC guidelines prior to use. The
following cell lines were used: K562 (chronic myelog-
enous leukemia, CML), HeLa (cervical cancer), Caco-2
(colorectal adenocarcinoma) and NCI-H358 (bronchioal-
veolar carcinoma). Adherent cells were cultured as mon-
olayers and maintained in Dulbecco’s Modifed Eagle
Medium (DMEM) supplemented with 10% fetal bovine
serum (FBS), 2 mM l-glutamine, 100 U/mL penicillin and
Acknowledgements We wish to thank kindly Dr Hana Čipčić Paljetak
and Dr Donatella Verbanac from the School of Medicine, University of
1 3

Molecular Diversity
13. Aytemir MD, Karakaya G (2012) Kojic acid derivatives. In:
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Zagreb, for investigating the antibacterial activity of compounds. We
would also like to thank the Croatian Science Foundation for support
of this work (Project IP-2014-09-7899).
14. Zirak M, Eftekhari-Sis B (2015) Kojic acid in organic synthesis.
Turk J Chem 39:439–496. https://doi.org/10.3906/kim-1502-55
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https://doi.org/10.2174/092986710792065027
Compliance with ethical standards
Conflict of interest We wish to confrm that there are no conficts of
interest associated with this publication.
17. Petrović Peroković V, Car Ž, Opačak-Bernardi T, Martin-
Kleiner I, Kralj M, Tomić S (2017) In vitro antiproliferative
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Afliations
Vesna Petrović Peroković1 · Željka Car1 · Andrea Usenik1 · Teuta Opačak‑Bernardi2 · Andrea Jurić3 · Srđanka Tomić1
1
3
Department of Chemistry, Faculty of Science, University
of Zagreb, Horvatovac 102a, 10000 Zagreb, Croatia
Department of Chemistry, Josip Juraj Strossmayer University
of Osijek, Cara Hadrijana 8/A, 31000 Osijek, Croatia
2
Faculty of Medicine, Josip Juraj Strossmayer University
of Osijek, Josipa Huttlera 4, 31000 Osijek, Croatia
1 3